This proposal is for continuation of a highly productive Program Project Grant currently in its 9th year. Nine investigators will study the molecular basis of neoplastic disease. Laboratory approaches to the problem of neoplasia are diverse but complementary. The scientific make-up of the group will encourage analysis of basic problems in tumor cell biology from the biochemical level to molecular genetics. Interactions at both the intellectual and technical levels make this cooperative effort much stronger and more economical than nine independent efforts. The growth of cells in normal, adult tissues is tightly regulated. Controls of cell proliferation and of differentiation are both aberrant in cancer cells; indeed the regulatory pathways for both processes may be intimately linked. Virtually all of the studies proposed here center on some aspect of this question of regulatory mechanisms. A priori, these controls may be positive or negative: investigations of both sorts of mechanisms suggested. We will use novel serum-free media to isolate and characterize primary populations of human breast cancer cells to screen by DNA transfer for genes that interfere with tumor forming ability. We will study the types and actions of negative intercellular signals regulating transformation. Potentially major negative controls on cell growth by interferon are investigated. The laboratory will investigate how thymidine kinase mRNA is produced, processed and degraded as an end point determinant of the important G1 phase of the cell cycle. Differentiation is subject to control by exogenous factors. Mutations affecting human epidermal cell differentiation will be investigated. The genetic control of how a preadipocyte cell becomes "locked" into a determined pathway of differentiation is to be explored. The genetic control differentiation of 3 malignant cellular systems will be studied: teratocarcinoma, pheochromocytoma, and colonic carcinoma. Both the teratocarcinoma and pheochromocytoma system also revert to a less malignant form upon their differentiation, stimulated by retinoic acid and nerve growth factor, respectively. Alterations of the mitochondria of colonic tumor cells will be a particular focus of research.